Losartan potassium, also known as 2-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-buphenyl]-4-yl]-1H-imidazole-5-methanol monopotassium salt, is a competitive AT1 angiotensin II receptor antagonist and has the following formula (I):

Activation of AT1 receptors in the outer membrane of vascular smooth muscle cells of the heart and arteries causes the tissues to constrict. AT1 receptors are activated by an octa-peptide, angiotensin II. Angiotensin II helps to maintain constant blood pressure despite fluctuations in a person's state of hydration, sodium intake and other physiological variables. Angiotensin II also performs the regulatory tasks of inhibiting excretion of sodium by the kidneys, inhibiting norephedrin reuptake and stimulating aldosterone biosynthesis. By inhibiting angiotensin II binding to AT1 receptors, losartan disrupts the vasoconstriction mediated by AT1 receptors. Blocking vasoconstriction by angiotensin II has been found to be beneficial to patients with hypertension.
In 1995, losartan became the first nonpeptide AT1 antagonist approved by the U.S. Food and Drug Administration for clinical use. In particular, losartan is approved for the treatment of hypertension alone or in combination with other antihypertensive agents. Losartan may be administered orally as its mono-potassium salt. Losartan potassium is available by prescription in tablet form as a sole active ingredient (Cozaar®: Merck) and as a co-active ingredient with hydrochlorothiazide (Hyzaar®: Merck).
U.S. Pat. No. 5,608,075, which is hereby incorporated by reference, discloses distinct crystalline structures, or forms, of losartan potassium which were designated Form I and Form II based on their respective thermal stability. As described in the '075 patent, losartan potassium Form II was prepared by heating Form I crystals in a differential scanning calorimetric (DSC) cell in an open pan to 255° C. at a heating rate of 10° C./minute under a nitrogen atmosphere. The '075 patent indicates that the change in crystal structure was detected as a change in the powder X-ray diffraction (PXRD) pattern. According to the '075 patent, Form II can be converted back into Form I at 25° C. in isopropanol, methyl ethyl ketone or ethyl acetate. Further, according to the '075 patent, Form I is the solid consistently obtained by solvent isolation, including recrystallization. Form II could only be obtained from DSC or related high temperature experiments.
The present invention relates to the solid state physical properties of losartan potassium. These properties can be influenced by controlling the conditions under which losartan potassium is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetric (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
In the '075 patent, losartan potassium Form I is prepared as follows. In one portion, a potassium hydroxide solution is added to losartan. The slurry is aged at room temperature for 30 minutes, during which time most of the solid dissolves. The cloudy solution is filtered and the solids collected on a sintered glass funnel. The pH of the filtrate is measured at 9.05. The aqueous solution is added slowly to a refluxing azeotropic mixture of cyclohexane/isopropanol (69° C.) whereupon the ternary azeotrope cyclohexane/isopropanol/water (64° C.) begins to distill. When the solution is dry, the temperature of the overhead rises to 69° C. and the potassium salt crystallizes. When the water content of the pot is <0.05% the distillation is halted and the white slurry is cooled to room temperature. Polymorph Form I, a white crystalline solid, is collected on a sintered glass funnel and washed with 10-15 ml of cyclohexane/isopropanol 67/33 and dried in a vacuum oven. The same method was used in U.S. Pat. No. 5,962,500 (Ex. 10), U.S. Pat. No. 5,663,187 (Ex. 10), U.S. Pat. No. 5,663,186 (Ex. 10) and U.S. Pat. No. 5,301,928 (Ex. 26, III).
Losartan potassium can be prepared by a variety of methods. For instance, in U.S. Pat. Nos. 5,128,355, 5,138,069 and 5,155,118, Example 316, Part D in all, losartan is isolated as its potassium salt by crystallization from a mixture of isopropyl alcohol and heptane. The crystals were reported to have a melting point above 250° C.
In U.S. Pat. No. 5,962,500, Example 5, and U.S. Pat. Nos. 5,206,374 and 5,310,928, Example 21 in both, losartan potassium salt was generated from a solution of losartan by extracting losartan from the solution with an adsorbent, treating the adsorbent with monobasic potassium phosphate and eluting losartan potassium from the adsorbent with 20% aqueous THF. The eluent was then concentrated and diluted with isopropyl alcohol, which yielded crystalline losartan potassium. According to the '500 patent, the product was also isolated by spray drying.
In U.S. Pat. Nos. 5,130,439, 5,206,374 and 5,310,928, Example 8 in all, losartan potassium salt was crystallized from a mixture of isopropyl alcohol, water and heptane. The product was collected by filtration, rinsed with heptane and dried at 50° C. in a vacuum oven to yield a white solid that decomposed at 267-269° C.
A crystalline form of a substance has well-defined physical properties; however, an amorphous form will exhibit a “smearing” of some of those properties due to the lack of long range structural order. An amorphous substance will produce a near featureless PXRD pattern although the diffraction pattern of a crystalline form of the same substance may have many well-resolved reflections. Generally, molecular interactions caused by tight crystal packing make a substance more thermally stable and less soluble than the substance would be in an amorphous state. Although thermal stability is a desirable characteristic of a pharmaceutical compound, it is often the case that increased, rather than decreased, solubility is desired. The rate of dissolution of an active ingredient in a patient's gastric fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. Increased solubility in aqueous fluids, therefore, can increase bioavailability. The effect that the solid-state has on bioavailability may be so significant that a crystalline form of a drug cannot be considered bioequivalent to the amorphous form.
In view of the foregoing, it would be desirable to have losartan potassium with improved bulk handling and dissolution properties.